The aged have increased susceptibility to and mortality from acute lung injury and sepsis. Sepsis is a systemic inflammatory response to infection and is the leading cause of acute lung injury. The average age of people in the USA is projected to rise, and the disease burden in this population is likely to increase substantially. There is therefore a need to develop targeted biologic therapies to improve outcomes. Specific Aims: We propose to investigate MKK3, a mitogen-activated protein kinase signaling molecule, as a therapeutic target in sepsis-induced lung injury in the aged. For the first time, we identifie MKK3 as a critical mediator of acute lung injury in young mice challenged with endotoxin (LPS), an established mediator of sepsis. In the process, we found that MKK3 modulates key pathways associated with aging such as Nrf1, Sirt1, mitochondrial health and mitophagy. The role of MKK3 in aged mouse models of sepsis and in people is unknown. Our hypothesis is that MKK3 is an important determinant of acute lung injury and sepsis during aging. We propose to show that MKK3 activity increases with aging and correlates with worse outcomes in older septic mice and people with lung injury. We will: 1. Determine the role of MKK3 in age-related susceptibility to lung injury and mortality in a mouse model of sepsis. 2. Correlate MKK3 activity to age, severity of sepsis and susceptibility to lung injury in critically ill septic people. Experimental Approach: We will use a mouse model of endotoxic shock and also study the peripheral blood monocytes from critically ill septic patients. Objective: Our overall goal is to identify MKK3 as a important mediator of sepsis and lung injury in the aged. By using both animal models and clinical samples, we will show that MKK3 is a potentially effective therapeutic target in sepsis.